Gibson G.E.,Brain and Mind Research Institute |
Thakkar A.,Brain and Mind Research Institute
Neurochemical Research | Year: 2017
Decades of research suggest that alterations in calcium are central to the pathophysiology of Alzheimer’s Disease (AD). Highly reproducible changes in calcium dynamics occur in cells from patients with both genetic and non-genetic forms of AD relative to controls. The most robust change is an exaggerated release of calcium from internal stores. Detailed analysis of these changes in animal and cell models of the AD-causing presenilin mutations reveal robust changes in ryanodine receptors, inositol tris–phosphate receptors, calcium leak channels and store activated calcium entry. Similar anomalies in calcium result when AD-like changes in mitochondrial enzymes or oxidative stress are induced experimentally. The calcium abnormalities can be directly linked to the altered tau phosphorylation, amyloid precursor protein processing and synaptic dysfunction that are defining features of AD. A better understanding of these changes is required before using calcium abnormalities as therapeutic targets. © 2017 Springer Science+Business Media New York
De Stefano N.,University of Siena |
Silva D.G.,Novartis |
Barnett M.H.,Brain and Mind Research Institute
CNS Drugs | Year: 2017
Brain atrophy occurs at a faster rate in patients with multiple sclerosis (MS) than in healthy individuals. In three randomized, controlled, phase III trials, fingolimod reduced the annual rate of brain volume loss (BVL) in patients with relapsing MS (RMS) by approximately one-third relative to that in individuals receiving placebo or intramuscular interferon beta-1a. Analysis of brain volume changes during study extensions has shown that this reduced rate of BVL is sustained in patients with RMS receiving fingolimod continuously. Subgroup analyses of the core phase III and extension studies have shown that reductions in the rate of BVL are observed irrespective of levels of inflammatory lesion activity seen by magnetic resonance imaging at baseline and on study; levels of disability at baseline; and treatment history. The rate of BVL in these studies was predicted independently by T2 lesion and gadolinium-enhancing lesion burdens at baseline, and correlations observed between BVL and increasing levels of disability strengthened over time. In another phase III trial in patients with primary progressive MS (PPMS), fingolimod did not reduce BVL overall relative to placebo; however, consistent with findings in RMS, there was a treatment effect on BVL in patients with PPMS with gadolinium-enhancing lesion activity at baseline. The association between treatment effects on BVL and future accumulation of disability argues in favor of measuring BVL on a more routine basis and with a more structured approach than is generally the case in clinical practice. Despite several practical obstacles, progress is being made in achieving this goal. © 2017, The Author(s).
Rice L.J.,Brain and Mind Research Institute |
Einfeld S.L.,Brain and Mind Research Institute |
Einfeld S.L.,University of Sydney
Current Opinion in Psychiatry | Year: 2015
To provide a review of the recent advances in the diagnosis and treatment of psychiatric disorders in Prader-Willi syndrome (PWS). RECENT FINDINGS: Research in the last 12 months has provided a descriptive prognosis of psychosis in PWS and highlighted the possible genes associated with the increased risk of psychosis for those with maternal uniparental disomy (mUPD). Several studies investigating social and communication skills have shown people with PWS to have difficulty with core, receptive and expressive language skills, interpreting emotional valence in faces, playing with children of their own age, understanding personal space and a developmental delay in the theory of mind. These social and communication deficits are often more pronounced in those with mUPD. Two recent clinical trials of oxytocin provide mixed results and highlight the need for an improved understanding of the neurobiological characteristics of the PWS brain. A recent pilot study suggests N-acetylcysteine may be a viable treatment for skin picking. SUMMARY: Recent advances have contributed to our understanding of the emotional and behavioural problems associated with PWS, and provided directions for further research. © 2015 Wolters Kluwer Health, Inc.
Bose A.,Appel Alzheimers Disease Research Institute |
Beal M.F.,Brain and Mind Research Institute
Journal of Neurochemistry | Year: 2016
Parkinson's disease (PD) is the second most common neurodegenerative disease. About 2% of the population above the age of 60 is affected by the disease. The pathological hallmarks of the disease include the loss of dopaminergic neurons in the substantia nigra and the presence of Lewy bodies that are made of α-synuclein. Several theories have been suggested for the pathogenesis of PD, of which mitochondrial dysfunction plays a pivotal role in both sporadic and familial forms of the disease. Dysfunction of the mitochondria that is caused by bioenergetic defects, mutations in mitochondrial DNA, nuclear DNA gene mutations linked to mitochondria, and changes in dynamics of the mitochondria such fusion or fission, changes in size and morphology, alterations in trafficking or transport, altered movement of mitochondria, impairment of transcription, and the presence of mutated proteins associated with mitochondria are implicated in PD. In this review, we provide a detailed overview of the mechanisms that can cause mitochondrial dysfunction in PD. We bring to the forefront, new signaling pathways such as the retromer-trafficking pathway and its implication in the disease and also provide a brief overview of therapeutic strategies to improve mitochondrial defects in PD. (Figure presented.) Bioenergetic defects, mutations in mitochondrial DNA, nuclear DNA gene mutations, alterations in mitochondrial dynamics, alterations in trafficking/transport and mitochondrial movement, abnormal size and morphology, impairment of transcription and the presence of mutated proteins associated with mitochondria are implicated in PD. In this review, we focus on the mechanisms underlying mitochondrial dysfunction in PD and bring to the forefront new signaling pathways that may be involved in PD. We also provide an overview of therapeutic strategies to improve mitochondrial defects in PD. This article is part of a special issue on Parkinson disease. © 2016 International Society for Neurochemistry
Brewer W.J.,University of Melbourne |
Lambert T.J.,Brain and Mind Research Institute |
Witt K.,University of Melbourne |
Dileo J.,Murdoch Childrens Research Institute |
And 4 more authors.
The Lancet Psychiatry | Year: 2015
Background: The first episode of psychosis is a crucial period when early intervention can alter the trajectory of the young person's ongoing mental health and general functioning. After an investigation into completed suicides in the Early Psychosis Prevention and Intervention Centre (EPPIC) programme, the intensive case management subprogramme was developed in 2003 to provide assertive outreach to young people having a first episode of psychosis who are at high risk owing to risk to self or others, disengagement, or suboptimal recovery. We report intensive case management model development, characterise the target cohort, and report on outcomes compared with EPPIC treatment as usual. Methods: Inclusion criteria, staff support, referral pathways, clinical review processes, models of engagement and care, and risk management protocols are described. We compared 120 consecutive referrals with 50 EPPIC treatment as usual patients (age 15-24 years) in a naturalistic stratified quasi-experimental real-world design. Key performance indicators of service use plus engagement and suicide attempts were compared between EPPIC treatment as usual and intensive case management, and psychosocial and clinical measures were compared between intensive case management referral and discharge. Findings: Referrals were predominately unemployed males with low levels of functioning and educational attainment. They were characterised by a family history of mental illness, migration and early separation, with substantial trauma, history of violence, and forensic attention. Intensive case management improved psychopathology and psychosocial outcomes in high-risk patients and reduced risk ratings, admissions, bed days, and crisis contacts. Interpretation: Characterisation of intensive case management patients validated the clinical research focus and identified a first episode of psychosis high-risk subgroup. In a real-world study, implementation of an intensive case management stream within a well-established first episode of psychosis service showed significant improvement in key service outcomes. Further analysis is needed to determine cost savings and effects on psychosocial outcomes. Targeting intensive case management services to high-risk patients with unmet needs should reduce the distress associated with pathways to care for patients, their families, and the community. Funding: National Health & Medical Research Council and the Colonial Foundation. © 2015 Elsevier Ltd.
Hart G.,Brain and Mind Research Institute |
Hart G.,University of Sydney |
Hart G.,University of New South Wales |
Panayi M.C.,University of New South Wales |
And 2 more authors.
Behaviour Research and Therapy | Year: 2014
Background: Benzodiazepines reduce the effectiveness of fear extinction in rodents and of exposure therapy in people suffering from anxiety disorders if given concomitantly with the behavioral treatment from its onset. The present experiments used rats to examine whether benzodiazepines had the same detrimental effect when given after some initial extinction had been conducted drug-free. Methods: Rats were trained to fear a context (Experiments 1 and 2) or discrete cue (Experiment 3) and were extinguished to the context or cue under a benzodiazepine (midazolam) or vehicle. Extinction occurred either continuously in one session, with the drug or vehicle administered prior to the onset, or divided into two sessions, with the drug or vehicle administered prior to the second session. Rats were then tested, drug-free, for fear of the context or CS. Results: Midazolam disrupted context and cue extinction when administered prior to the initial session but failed to disrupt extinction when given prior to the second session. Conclusions: The results in an animal model confirm that the effectiveness of extinction can be reduced when combined with benzodiazepines. They also suggest that the effectiveness of extinction will not be reduced when combined with a benzodiazepine if the patient has undergone some initial extinction drug-free. © 2014 Elsevier Ltd.
Sethi S.,University of Sydney |
Campbell A.J.,University of Sydney |
Ellis L.A.,Brain and Mind Research Institute
Journal of Technology in Human Services | Year: 2010
Despite the efficacy of cognitive-behavioral therapy (CBT) in treating adolescent anxiety, few sufferers seek treatment. Barriers to accessing psychologists include a shortage of skilled therapists, long waiting lists, and affordability. The Internet is a medium possibly able to address issues of accessibility and affordability. This study aimed to assess the efficacy of online therapy in the treatment and prevention of adolescent anxiety and depression. Participants (N1/438) were randomly allocated to one of four conditions: online CBT, face-to-face CBT, combined face-to-face=online CBT, and control. Combined face-to-face=online CBT is more effective in treating symptoms of depression and anxiety compared to stand-alone online or face-to-face therapy. The present study suggests that for those who are unable to access face-to-face therapy, computerized therapy may be a viable option. This is an important finding, especially in light of current capacity to treat and accessibility problems faced in the treatment of adolescent depression and anxiety. © Taylor & Francis Group, LLC.
Hardy T.A.,University of Sydney |
Hardy T.A.,Brain and Mind Research Institute |
Miller D.H.,University College London
The Lancet Neurology | Year: 2014
Baló's concentric sclerosis is often regarded as a rare variant of multiple sclerosis. Patients with this disorder present with acute or subacute neurological deterioration, with MRI showing one or more concentrically multilayered ring-like lesions usually in the cerebral white matter. Historically, Baló's concentric sclerosis was thought fatal in all cases. However, the availability of MRI has led to a better appreciation of the variable natural history of patients presenting with radiologically evident Baló lesions and the clinical association with multiple sclerosis and, less often, with other neurological disorders. Important advances have increased understanding of the immunopathogenic mechanisms associated with the formation of Baló lesions. However, how to treat an acute lesion and when or whether to start treatment are less well understood, although for patients with Baló lesions who also fulfil standard diagnostic criteria for multiple sclerosis, our opinion is that treatment with multiple sclerosis disease-modifying therapy would seem reasonable. © 2014 Elsevier Ltd.
Forgacs P.B.,Brain and Mind Research Institute |
Forgacs P.B.,Rockefeller University |
Conte M.M.,Rockefeller University |
Fridman E.A.,Rockefeller University |
And 6 more authors.
Annals of Neurology | Year: 2014
Objective: Standard clinical characterization of patients with disorders of consciousness (DOC) relies on observation of motor output and may therefore lead to the misdiagnosis of vegetative state or minimally conscious state in patients with preserved cognition. We used conventional electroencephalographic (EEG) measures to assess a cohort of DOC patients with and without functional magnetic resonance imaging (fMRI)-based evidence of commandfollowing, and correlated the findings with standard clinical behavioral evaluation and brain metabolic activity.Methods: We enrolled 44 patients with severe brain injury. Behavioral diagnosis was established using standardized clinical assessments. Long-term EEG recordings were analyzed to determine wakeful background organization and presence of elements of sleep architecture. A subset of patients had fMRI testing of command-following using motor imagery paradigms (26 patients) and resting brain metabolism measurement using 18fluorodeoxyglucose positron emission tomography (31 patients).Results: All 4 patients with fMRI evidence of covert command-following consistently demonstrated well-organized EEG background during wakefulness, spindling activity during sleep, and relative preservation of cortical metabolic activity. In the entire cohort, EEG organization and overall brain metabolism showed no significant association with bedside behavioral testing, except in a few cases when EEG was severely abnormal.Interpretation: These findings suggest that conventional EEG is a simple strategy that complements behavioral and imaging characterization of DOC patients. Preservation of specific EEG features may be used to assess the likelihood of unrecognized cognitive abilities in severely brain-injured patients with very limited or no motor responses. © 2014 American Neurological Association.
Faraco G.,Brain and Mind Research Institute
Hypertension | Year: 2013
Endothelin-1 (ET1) is a potent vasoconstrictor peptide implicated in the cerebrovascular alterations occurring in stroke, subarachnoid hemorrhage, and brain trauma. Brain or circulating levels of ET1 are elevated in these conditions and in risk factors for cerebrovascular diseases. Most studies on the cerebrovascular effects of ET1 have focused on vascular smooth muscle constriction, and little is known about the effect of the peptide on cerebrovascular regulation. We tested the hypothesis that ET1 increases cerebrovascular risk by disrupting critical mechanisms regulating cerebral blood flow. Male C57Bl6/J mice equipped with a cranial window were infused intravenously with vehicle or ET1, and somatosensory cortex blood flow was assessed by laser Doppler flowmetry. ET1 infusion increased mean arterial pressure and attenuated the blood flow increase produced by neural activity (whisker stimulation) or neocortical application of the endothelium-dependent vasodilator acetylcholine but not A23187. The cerebrovascular effects of ET1 were abrogated by the ET(A) receptor antagonist BQ123 and were not related to vascular oxidative stress. Rather, the dysfunction was dependent on Rho-associated protein kinase activity. Furthermore, in vitro studies demonstrated that ET1 suppresses endothelial nitric oxide (NO) production, assessed by its metabolite nitrite, an effect associated with Rho-associated protein kinase-dependent changes in the phosphorylation state of endothelial NO synthase. Collectively, these novel observations demonstrate that increased ET1 plasma levels alter key regulatory mechanisms of the cerebral circulation by modulating endothelial NO synthase phosphorylation and NO production through Rho-associated protein kinase. The ET1-induced cerebrovascular dysfunction may increase cerebrovascular risk by lowering cerebrovascular reserves and increasing the vulnerability of the brain to cerebral ischemia.